Numerous past studies have shown that hepatocyte proliferation during liver regeneration and carcinogenesis is associated with the appearance of blood born factors that stimulate hepatocyte proliferation. We have found that there are only four substances in the serum that stimulate hepatocyte proliferation. These are Hepatopoietin A. Hepatopoietin B, Epidermal Growth Factor (EGF), and Norepinephrine. Fractions with Hepatopoietin A activity treated with trypsin increase their activity and the new activity is associated with a much smaller molecular weight. In addition we found that many hepatoma cell lines are secrete Hepatoma Derived Growth Factors (HDGF's) that also stimulate hepatocyte proliferation and bind to the EGF receptor. The two hepatopoietins and the HDGF's are at the end stages of their purification. The projects aim to provide a comprehensive evaluation of the peptide growth factors in regenerative and neoplastic liver growth. The two hepatopoietins and the HDGF's will be completely purified and characterized. The interactions of these factors with other hormones will be examined. The existence of receptors for these growth factors will be searched. The expression of the genes encoding for these factors will be also assessed in liver regeneration and neoplasia. Interactions of these factors will TGFb will be given particular emphasis. New studies will also attempt to identify the existence of other factors in the rat plasma or serum (besides TGFb) that inhibit hepatocyte proliferation, following our findings that the serum from control rats contain inhibitory activities for hepatocyte proliferation that are not present in the serum from hepatectomized rats. Given the fact that HPTA activity increases affter protease treatment and in view of previous studies emphasizing the presence of protease activities on hepatocyte plasma membranes, the role of specific hepatocyte plasma membrane proteases in the activation of HPTA during liver regeneration will also be assessed. Additional studies will be performed to assess the role of EGF itself as a potential mitogen during liver regeneration.